Numerous compositions for controlled release of an active substance, e.g. a pharmaceutically active powder, into an aqueous medium, e.g. the human gastrointestinal tract, are known. Such controlled release may for example be obtained by embedding the active substance in a matrix of an insoluble substance from which the active substance will gradually diffuse. Sustained release of an active substance contained in a tablet core may also be achieved by applying to the core a semi-permeable coating through which water and dissolved active substance may diffuse or an insoluble coating provided with a hole through which the active substance is released. Gradual release of an active substance may furthermore be obtained by microencapsulating particles of an active substance in one or more layers of film which may be of various types, e.g. of a type which mediates diffusion of the active substance or release thereof in the intestines.
WO 89/09066 discloses a composition for controlled delivery of an active substance into an aqueous phase by erosion at a substantially constant rate of a surface or surfaces of the composition, the composition containing a) a matrix of a crystalline polyethylene glycol (PEG) polymer with a molecular weight of at least 20,000 daltons, b) at least one non-ionic emulsifier dispersed in the polyethylene glycol matrix in an amount of 2-50% by weight of the crystalline polymer and the non-ionic emulsifier, the non-ionic emulsifier having at least one domain which is compatible with the polyethylene glycol polymer and being selected from fatty acid esters and fatty alcohol ethers, and c) at least one active substance substantially homogeneously dispersed in the polyethylene glycol matrix and/or located in geometrically well-defined zones within the composition, the non-ionic emulsifier and/or the active substance reducing the water affinity of domains between grains and in cracks in the crystalline polymer matrix and in the crystalline polymer matrix itself, thereby substantially eliminating water diffusion in the interface between the polymer crystals, so that the erosion is predominantly effected by the dissolving action of an aqueous medium on a surface or surfaces of the composition exposed to the medium.
Other controlled release compositions based on this principle are disclosed in WO 91/04015, which relates to compositions that provide a regulated non-initial burst release of an active substance at a predetermined time.
WO 95/22962 describes controlled release compositions with a matrix of the type described in WO 89/09066, the compositions being further provided with a cellulose derivative-based coating having at least one opening exposing at least one surface of the matrix, the coating being one which crumbles and/or erodes upon exposure to the aqueous medium at a rate which is equal to or slower than the rate at which the matrix erodes in the aqueous medium. This allows exposure of the surface of the matrix to the aqueous medium to be controlled.
U.S. Pat. No. 5,683,719 describes controlled release compositions in the form of extruded rods or tubes comprising an active material, microcrystalline cellulose and clay, the rods or tubes being coated with a material allowing dissolution of the active material to proceed in a controlled manner and allowing the rods or tubes to retain their structural integrity during the release period.
While the known controlled release compositions such as those described above provide great advantages in terms of allowing controlled, e.g. zero order, delivery of an active substance or release of an active substance according to a predetermined pattern, certain problems are nevertheless encountered in connection with oral delivery of active substances in this manner due to the very substantial differences in the chemical and physical environment found in different parts of the gastrointestinal system. Especially when a constant zero order release of an active substance is desired, one is faced with the problem that the composition first passes through the stomach, which has a very low pH, typically about 2, together with a high degree of agitation due to peristaltic movements and the presence of a relatively large amount of low viscosity liquids, and then to the intestines, which have a substantially neutral pH of about 7 and a low degree of agitation. A further complication in this regard is the fact that the absorption capability of the stomach is in many cases different from, typically much greater than, that of the intestines. As a result of these two factors, the delivery rate of an active substance when a given controlled release composition is present in the stomach is normally several times greater than the delivery rate for the same composition when it is present in the intestines. This is obviously a significant disadvantage when zero order release is desired over an extended period of time, i.e. several hours. An additional problem is that the residence time of a composition in the stomach can vary tremendously, e.g. from about 1 hour to about 4 hours or more. Thus, providing zero order release by merely adapting part of a controlled release composition for a given release rate under a given set of conditions in the stomach and another part of the composition for a different release rate under another set of conditions in the intestines is not possible as such, because there is no way of knowing in advance what the residence time in the stomach will be in any given case.
The present invention is a further development based on the inventions disclosed in WO 89/09066, WO 91/04015 and WO 95/22962. In particular, it has surprisingly been found that it is possible to regulate the release profile of these and similar controlled release compositions containing an active substance by incorporating into the matrix a release modifier that functions to regulate erosion of the matrix in the acidic pH range found in the stomach, while at the same time allowing release of the active substance after the composition reaches the intestines.